Intrathecal methotrexate is widely used for the treatment of brain tumors, meningeal leukemia, lymphomatous meningitis and other neoplasms metastatic to the central nervous system. Unfortunately, this modality may have limited effect against neoplastic cells located more than seven to 20 millimeters from the surface of the brain. Furthermore, intrathecal methotrexate has resulted in serious neurotoxicity such as paraplegia and necrotizing leukoencephalopathy. Other disadvantages include the effort, discomfort and complications of frequent lumbar punctures. The goal of this project is to improve the therapeutic index of intrathecal methotrexate therapy. The approaches that will be taken include: 1) correlation of cerebrospinal-fluid antifolate concentrations with therapeutic and toxic effects, 2) identification of patient characteristics that influence the central-nervous-system pharmacokinetics of methotrexate, 3) pharmacologic evaluation of the hyperbaric injection technique, 4) additional clinical experience with intraventricular chemotherapy via the Ommaya reservoir, 5) phase 2 and phase 3 trials of intrathecal aminopterin. Murine and primate models will be used to develop and test new methods of central-nervous-system chemotherapy. Methotrexate concentration will be determine by a modification of the dihydrofolate-reductase inhibition assay which permits more rapid analysis than previously available and which can be adopted by any major clinical chemistry laboratory. The ultimate objective is to eliminate the need for intrathecal methotrexate. This possibility will be explored by infusing very high doses (e.g. 11040 mg/sq.m) of methotrexate intravenously for 42 hr periods, followed by citrovorum rescue.